Regulatory Relationship of Glucose Metabolism and Cerebral Slow Wave Activity

葡萄糖代谢与大脑慢波活动的调节关系

• 批准号: 8416950
• 负责人: Jonathan P Wisor
• 金额: $ 31.88万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416950
• 关键词: Address; Affect; Behavioral; Biochemical; Brain; Cerebral cortex; Cerebrum; Chemicals; Data; Disease; Documentation; Electroencephalogram; Etiology; Feedback; Genetic; Glucose; Glycogen; Glycolysis; Goals; Health; Intervention; Lead; Measures; Mediating; Mediator of activation protein; Mental disorders; Metabolic; Metabolism; Mind; Monitor; Mouse Strains; Mus; Neck; Neurobiology; Neurons; Outcome; Personal Satisfaction; Physiological; Population; Process; Public Health; Publishing; Pyruvate; REM Sleep; Regulation; Relative (related person); Research; Risk Factors; Role; Sensory; Series; Sleep; Sleep Deprivation; Sleep Disorders; Slow-Wave Sleep; Testing; Time; Vibrissae; Wakefulness; Well in self; Work; barrel cortex; design; enantiomer; genetic strain; glucose metabolism; improved; innovation; insight; non rapid eye movement; novel; optogenetics; research study; response; sleep regulation; somatosensory; tool

DESCRIPTION (provided by applicant): Poor-quality sleep and sleep insufficiency are significant risk factors for physical and mental illness and are of major public-health concern. Much effort to date has rightfully focused on the roles of subcortical populations of neurons in the regulation of biochemical and electroencephalographic responses to sleep insufficiency. Despite the body of evidence that sleep is regulated locally within functional circuits of the cerebral cortex, there is a relative paucity of experimental data on the regulation of sleep by mechanisms intrinsic to the cerebral cortex. The objective of this proposal is to determine the extent to which glycolytic metabolism within the cerebral cortex regulates electroencephalographic slow wave activity during sleep. The central hypothesis is that the temporal dynamics of slow wave activity during non-rapid eye movement sleep are regulated in a feedback relationship between slow wave activity and the glucose metabolite, lactate in the cerebral cortex. The rationale for the research proposed here is that documentation of a feedback relationship between lactate concentration and slow wave activity in the electroencephalogram will improve our understanding of the cerebral effects of sleep insufficiency and will identify the regulation of cerebral glucose utilization as a function of slep slow waves. The working hypothesis for the proposed experiments is that accumulation of lactate in the cerebral cortex during wakefulness promotes slow wave activity during subsequent sleep and slow wave activity during sleep, in turn, promotes a decline in lactate levels. We propose four specific aims designed to document this relationship. The first aim is to determine the extent to which genetic differences in the temporal dynamics of sleep slow wave activity are paralleled by genetic differences in the sleep state-dependent dynamics of lactate in the cerebral cortex. The second aim is to determine whether excessive activation of discrete functional units in the cerebral cortex, a manipulation that increases slow wave activity during subsequent sleep, also increases the rate of lactate accumulation in the cerebral cortex. The third aim is to determine whether manipulations of slow wave activity in the cerebral cortex alter lactate levels independently of sleep state. The final aim is to determine whether the processing of lactate as a glycolytic fuel by the cerebral cortex modulates sleep slow wave activity. The proposed experiments are innovative, in our opinion, because they have the potential to identify a novel regulatory relationship between sleep and cerebral glucose metabolism. The results are expected to collectively establish that sleep slow wave activity serves to release the lactate accumulated in the cerebral cortex during wakefulness. The experiments may yield novel insights into the etiology of sleep disorders and may yield novel tools for intervention in disorders of cerebral metabolism.

描述(由申请人提供)：睡眠质量差和睡眠不足是身体和精神疾病的重要风险因素，是重大的公共卫生问题。到目前为止，许多努力都正确地集中在皮质下神经元群体在调节对睡眠不足的生化和脑电反应中的作用。尽管有大量证据表明，睡眠在大脑皮层的功能回路中受到局部调节，但关于大脑皮层固有机制对睡眠的调节的实验数据相对较少。这项建议的目的是确定大脑皮层内的糖酵解代谢在多大程度上调节睡眠期间的脑电慢波活动。中心假说是，在非快速眼动睡眠中，慢波活动的时间动力学是通过慢波活动与大脑皮层中葡萄糖代谢产物乳酸之间的反馈关系来调节的。这项研究的理论基础是，记录脑电中乳酸浓度和慢波活动之间的反馈关系将有助于我们更好地理解睡眠不足对大脑的影响，并将大脑葡萄糖利用的调节确定为SLEP慢波的函数。提出的实验的工作假设是，清醒时大脑皮层中乳酸的积累促进了随后睡眠中的慢波活动，而睡眠中的慢波活动反过来又促进了乳酸水平的下降。我们提出了四个旨在记录这种关系的具体目标。第一个目标是确定睡眠慢波活动时间动态的遗传差异在多大程度上与大脑皮层中依赖睡眠状态的乳酸动态的遗传差异平行。第二个目的是确定大脑皮层中离散功能单元的过度激活是否也会增加大脑皮层中乳酸的积累率。第三个目标是确定大脑皮层慢波活动的操作是否独立于睡眠状态改变乳酸水平。最终目的是确定大脑皮层将乳酸作为糖酵解燃料处理是否会调节睡眠慢波活动。我们认为，拟议的实验具有创新性，因为它们有可能确定睡眠和大脑葡萄糖代谢之间的一种新的调节关系。这些结果有望共同证实，睡眠慢波活动有助于释放清醒时积累在大脑皮层的乳酸。这些实验可能会为睡眠障碍的病因提供新的见解，并可能为干预大脑代谢障碍提供新的工具。